Efficacy and safety of a new low-volume PEG with citrate and simethicone bowel preparation for pediatric elective colonoscopy: Phase 3 RCT.

Background and study aims Currently available polyethylene glycol (PEG)-based preparations continue to represent a challenge in children. The aim of this study was to compare the efficacy and safety of a new low-volume PEG preparation with a conventional PEG-electrolyte solution (PEG-ES) in children and adolescents. Patients and methods This was a multicenter, randomized, observer-blind, parallel-group, phase 3 clinical trial, where patients were randomized between PMF104 (Clensia) and a conventional PEG-ES (Klean-Prep), and stratified by age stratum (2 to <6; 6 to < 12;12 to <18 years). The primary endpoint was to test the non-inferiority of PMF104 versus PEG-ES, in terms of colon cleansing. Safety, tolerability, acceptability, palatability, and compliance were also assessed. Efficacy endpoints were analyzed in the per protocol set (PPS) and full analysis set (FAS) and safety and tolerability endpoints in the safety set (SAF). Results Of the 356 patients enrolled, 258 were included in the PPS, 346 in the FAS, and 351 in the SAF. Non-inferiority of PMF104 was confirmed for children aged > 6 years and for all age groups in PPS and FAS, respectively. Optimal compliance was reported more frequently in the PMF104 than in the PEG-ES group, in both PPS (86.1% vs. 68.4%) and FAS (82.9% vs. 65.3%). Both preparations were equally safe and tolerable. Palatability and acceptability were considered better in the PMF104 group than in the PEG-ES group (27.1% vs. 15.3% and 15.3% vs. 3.5%, respectively). Conclusions In children aged 6 to 17 years, the new low-volume product PMF104 is non-inferior to the reference PEG-ES in terms of bowel cleansing, safety, and tolerability, with slightly better results in compliance, palatability, and acceptability.

Treatment of pediatric heterozygous familial hypercholesterolemia 7 years after the EAS recommendations: Real-world results from a large French cohort.

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) predisposes to premature cardiovascular diseases. Since 2015, the European Atherosclerosis Society has advocated initiation of statins at 8-10 years of age and a low-density lipoprotein cholesterol (LDL-C) target of <135 mg/dL. Longitudinal data from large databases on pharmacological management of pediatric HeFH are lacking. OBJECTIVE: Here, we describe treatment patterns and LDL-C goal attainment in pediatric HeFH using longitudinal real-world data. METHODS: This was a retrospective and prospective multicenter cohort study (2015-2021) of children with HeFH, diagnosed genetically or clinically, aged <18 years, and followed up in the National French Registry of FH (REFERCHOL). Data on the study population as well as treatment patterns and outcomes are summarized as mean±SD. RESULTS: We analyzed the data of 674 HeFH children (age at last visit: 13.1 ± 3.6 years; 82.0 % ≥10 years; 52.5 % females) who were followed up for a mean of 2.8 ± 3.5 years. Initiation of lipid-lowering therapy was on average at 11.8 ± 3.0 years of age for a duration of 2.5 ± 2.8 years. At the last visit, among patients eligible for treatment (573), 36 % were not treated, 57.1 % received statins alone, 6.4 % statins with ezetimibe, and 0.2 % ezetimibe alone. LDL-C was 266±51 mg/dL before treatment and 147±54 mg/dL at the last visit (-44.7 %) in treated patients. Regarding statins, 3.3 %, 65.1 %, and 31.6 % of patients received high-, moderate-, and low-intensity statins, respectively. Overall, 59 % of children on statin therapy alone and 35.1 % on bitherapy did not achieve the LDL-C goal; fewer patients in the older age group did not reach the treatment goal. CONCLUSION: Pediatric patients with FH followed up in specialist lipid clinics in France receive late treatment, undertreatment, or suboptimal treatment and half of them do not reach the therapeutic LDL-C goal. Finding a more efficient framework for linking scientific evidence to clinical practice is needed.

Prevalence and Etiologies of Renal and Urinary Manifestations in a Large Cohort of Children With Inflammatory Bowel Disease.

BACKGROUND AND OBJECTIVES: Renal and/or urinary manifestations (RUM) have been reported in pediatric patients with inflammatory bowel disease (IBD) but their incidence is unknown. The aims of this study were to assess the prevalence and causes of these manifestations in children with IBD and determine the causal link with 5-aminosalicylic acid (5-ASA) treatment. METHODS: A retrospective observational study was performed with children with diagnosis of IBD. All children with RUM during follow-up and/or impaired renal function [estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m 2 ] were identified. RESULTS: Of 228 included patients, 9 (3.9%) had a RUM during follow-up [follow-up: 5 years (1-12 years)] at a median age of 16 years (8-17 years). It concerned 7 of 171 patients with Crohn disease and 2 of 57 with ulcerative colitis. Seven patients were taking 5-ASA at the time of the RUM. Only 1 of them had an iatrogenic renal complication related to this treatment. Patients with RUM had a more severe disease with increased anti-tumor necrosis factor-α use ( P = 0.031), more abscesses ( P = 0.003), and a higher rate of digestive surgery ( P = 0.04). For the whole cohort, a significant decrease in eGFR was found during follow-up (121 vs 107 mL/min/1.73 m 2 , P < 0.001). At the end of follow-up, 38 of 202 (19%) patients had an eGFR < 90 mL/min/1.73 m 2 . CONCLUSION: In children with IBD, RUM can occur, independently of treatment with 5-ASA. During follow-up, a significant decrease in eGFR was observed. We suggest monitoring renal function in all patients with IBD.

Factors Predicting Statin Initiation During Childhood in Familial Hypercholesterolemia: Importance of Genetic Diagnosis.

OBJECTIVE: To identify childhood and parental factors associated with initiation of statin therapy in children with heterozygous familial hypercholesterolemia (HeFH), including underlying genetic diagnosis or parental premature atherosclerotic cardiovascular disease (ASCVD). STUDY DESIGN: This multicenter cohort study included 245 HeFH child-parent pairs from the REFERCHOL national register (2014-2020). Demographic and clinical characteristics at the last visit were collected. Vascular disease in parents was defined as a history of ASCVD, and/or a coronary artery calcium score >100, and/or stenosis of >50% in at least carotid artery. Statistical analyses included descriptive analysis, logistic regression for univariate and multivariate effects of statins, and a sensitivity analysis combining the characteristics of children and parents. RESULTS: Among the 245 children in the study cohort, 135 (58%), with a mean age of 14 ± 3 years, were treated with a statin. In multivariable analysis, the predictive childhood factors associated with statin treatment were genetic diagnosis (OR, 2.5; 95% CI, 1.3 to 4.9; P = .01), older age (OR, 4.4; 95% CI, 1.8-10.6; P = .01), more than 2 visits (OR, 2.36; 95% CI, 1.18-4.73; P = .015), and longer duration of follow-up (OR, 1.3; 95% CI, 1.1-1.6; P < .001). The predictive parental factor associated with childhood treatment was the presence of vascular disease (OR, 2.4; 95% CI, 1.0-5.7; P = .04). CONCLUSIONS: HeFH confirmed by DNA testing during childhood and a history of vascular disease in parents were independently associated with statin treatment in children with HeFH. Genetic diagnosis may be useful for cardiovascular prevention in children.

[Gluten intolerance in infants and children: diagnosis and what recommendations?] / Intolérance au gluten en pédiatrie : diagnostic et recommandations.

Gluten intolerance in infants and children: what diagnosis and what recommendations? Gluten intolerance or celiac disease is a relatively common pathology that is still underdiagnosed in pediatrics due to its heterogeneous presentation. Apart from the classic form of malabsorption with diarrhea and growth retardation, pathology should be sought in the event of a family history of celiac disease, autoimmunity and in the context of certain syndromes. Other clinical or laboratory signs should also suggest the diagnosis. Any suspicion should lead to assays for total IgA and anti- transglutaminase IgA. If the child is symptomatic or not, the absence of upper gastrointestinal endoscopy with biopsies is possible to make the diagnosis after agreement of the family, if the levels of anti-transglutaminase IgA are greater than 10 times the upper limit of normal, and if the anti-endomysium IgA, assayed on a second sample, are also positive. Management is based on a strict gluten-free diet.

Intolérance au gluten en pédiatrie : diagnostic et recommandations. L'intolérance au gluten, ou maladie coeliaque, est relativement fréquente mais reste sous-diagnostiquée en pédiatrie du fait de sa présentation hétérogène. En dehors du tableau classique de malabsorption, avec diarrhée et retard de croissance, elle doit être recherchée en cas d'antécédents familiaux de maladie coeliaque, d'auto-immunité et dans le cadre de certains syndromes. D'autres signes cliniques ou biologiques doivent également évoquer ce diagnostic. Toute suspicion impose le dosage des IgA totales et des IgA antitransglutaminase. Que l'enfant soit symptomatique ou non, si les taux d'IgA antitransglutaminase sont supérieurs à 10 fois la limite supérieure à la normale, et si les IgA anti-endomysium, dosées sur un deuxième prélèvement, sont également positives, le diagnostic peut être posé sans endoscopie digestive haute avec biopsies, après accord de la famille. La prise en charge repose sur un régime d'éviction strict du gluten à vie.

[Chronic aqueous diarrhea in children: An unusual etiology]. / Diarrhée aqueuse chronique chez l'enfant : une étiologie à ne pas méconnaître.

Peripheral neuroblastic tumors are the most common extracranial solid tumors in children. On the other hand, diarrheal neuroblastic tumors are quite rare and not easy to diagnose in the early stage. We report a case of neuroblastic tumor in a 2-year old girl presenting with aqueous diarrhea caused by paraneoplasic secretion of VIP.

Feasibility of open abdomen surgery treatment for near fatal necrotizing enterocolitis in preterm infants.

INTRODUCTION: Necrotizing Enterocolitis (NEC) remained a dramatic complication leading to death or neonatal morbidities in preterms. For some, Intra-Abdominal Hypertension (IAH) and Abdominal Compartment Syndrome worsened the multi-organ failure. An open abdomen surgery could be an alternative to conventional surgical treatment to move beyond this stage. OBJECTIVES: To retrospectively describe the clinical course, pre- and post-operative features of preterms suffering from severe NEC with IAH treated by open abdomen surgery and referred to our center from October 2007 to September 2019. Our secondary objective is to identify various risk factors for mortality in this population. METHODS: Data on neonatal, clinical, biological, pre and post-operative features and outcome were collected. Univariate analyses were performed to compare their pre and post-operative features stratifying on outcome. RESULTS: Among 29 included patients, 14 (48%) survived to discharge without short bowel syndrome. Death was associated with an earlier postnatal age at NEC (16.3 ± 9.1 versus 31.3 ± 25.9 days; p = 0.004) and followed a withdrawal of treatment in 60% of cases. Surgery was associated with a significant improvement of respiratory and hemodynamic features (decrease of mean ventilator pressure from 13.1 ± 5.4 to 11.3 ± 4.0 cmH2O, p < 0.001), oxygen requirement (mean FiO2 decreased from 65.0% ± 31.2 to 49.0% ± 24.6, p < 0.001) and inotropic score (from 38.6 ± 70.1 to 29.9 ± 64.3, p < 0.001). In the survival group, pre and post-operative findings exhibited a significant increase of serum lactate concentrations from 2.7 ± 1.6 to 11.0 ± 20.3 mmol/L (p = 0.02) but a similar pH. CONCLUSION: Open abdomen surgery could be considered to rescue preterms with near fatal NEC. IAH and Abdominal Compartment Syndrome in these preterms should be investigated through further studies. LEVEL OF EVIDENCE: Level III.

A European Survey on Digestive Perianastomotic Ulcerations, a Rare Crohn-like Disorder Occurring in Children and Young Adults.

OBJECTIVES: Digestive perianastomotic ulcerations (DPAU) resembling Crohn disease lesions are long-term complications of intestinal resections, occurring in children and young adults. They are known to be uncommon, severe and difficult to treat. METHODS: In the absence of recommendations, we performed a large European survey among the members of the ESPGHAN working group on inflammatory bowel disease (IBD) in order to collect the experience of expert pediatric gastroenterologists on DPAU. RESULTS: Fifty-one patients (29 boys and 22 girls) were identified from 19 centers in 8 countries. Most patients were followed after necrotizing enterocolitis (n = 20) or Hirschsprung disease (n = 11). The anastomosis was performed at a median age (interquartile range) of 6 [1-23] months, and first symptoms occurred 39 [22-106] months after surgery. Anemia was the most prevalent symptom followed by diarrhea, abdominal pain, bloating, and failure to thrive. Hypoalbuminemia, elevated CRP, and fecal calprotectin were common. Deep ulcerations were found in 59% of patients usually proximally to the anastomosis (68%). During a median follow-up of 40 [19-67] months, treatments reported to be the most effective included exclusive enteral nutrition (31/35, 88%), redo anastomosis (18/22, 82%), and alternate antibiotic treatment (37/64, 58%). CONCLUSIONS: Unfortunately, persistence of symptoms, failure to thrive, and abnormal laboratory tests at last follow-up in most of patients show the burden of DPAU lacking optimal therapy and incomplete understanding of the pathophysiology.

Clinical Remission and Psychological Management are Major Issues for the Quality of Life in Pediatric Crohn Disease.

OBJECTIVES: Crohn disease (CD) can affect patient's quality of life (QOL) with physical, social, and psychological impacts. This study aimed to investigate the QOL of children with CD and its relationship with patient and disease characteristics. METHODS: Children ages from 10 to 17 years with diagnosed CD for more than 6 months were eligible to this cross-sectional study conducted in 35 French pediatric centers. QOL was assessed by the IMPACT-III questionnaire. Patient and disease characteristics were collected. RESULTS: A total of 218 children (42% of girls) were included at a median age of 14 years (interquartile range [IQR]: 13--16). Median duration of CD was 3.2 years (IQR: 1.7-5.1) and 63% of children were in clinical remission assessed by wPCDAI. Total IMPACT-III score was 62.8 (±11.0). The lowest score was in "emotional functioning" subdomain (mean: 42.8 ±â€Š11.2). Clinical remission was the main independent factor associated with QOL of children with CD (5.74 points higher compared with those "with active disease", 95% confidence interval [CI] 2.77--8.70, P < 0.001). Age of patient at the evaluation was found negatively correlated with QOL (-0.76 per year, 95% CI: -1.47 to -0.06, P = 0.009). Presence of psychological disorders was associated with a lower QOL (-9.6 points lower to those without, 95% CI: -13.34 to -5.86, P < 0.0001). Total IMPACT-III and its subdomains scores were not related to sex, disease duration, or treatments. CONCLUSIONS: These results not only confirm that clinical remission is a major issue for the QOL of patients, but also highlights the importance of psychological care.

Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency.

Mutations in the tetratricopeptide repeat domain 7A (TTC7A) gene cause very early onset inflammatory bowel diseases (VOIBD) or multiple intestinal atresia associated with immune deficiency of various severities, ranging from combined immune deficiency to mild lymphopenia. In this manuscript, we report the clinical, biological and molecular features of a patient born from consanguineous parents, presenting with recurrent lymphoproliferative syndrome and pan-hypergammaglobulinemia associated with chronic intestinal pseudo obstruction (CIPO). Genetic screening revealed the novel c.974G>A (p.R325Q) mutation in homozygosity in the TTC7A gene. The patient's phenotype differs significantly from that previously associated with TTC7A deficiency in humans. It becomes closer to the one reported in the ttc7a-deficient mice that invariably develop a proliferative lymphoid and myeloid disorder. Functional studies showed that the extreme variability in the clinical phenotype couldn't be explained by the cellular phenotype. Indeed, the patient's TTC7A mutation, as well as the murine-ttc7 mutant, have the same functional impact on protein expression, DNA instability and chromatin compaction, as the other mutations that lead to classical TTC7A-associated phenotypes. Co-inheritance of genetic variants may also contribute to the unique nature of the patient's phenotype. The present case report shows that the clinical spectrum of TTC7A deficiency is much broader than previously suspected. Our findings should alert the physicians to consider screening of TTC7A mutations in patients with lymphoproliferative syndrome and hypergammaglobulinemia and/or chronic intestinal pseudo-obstruction.

Efficacy and Safety of the Local Application of Mitomycin C to Recurrent Esophageal Strictures in Children.

OBJECTIVES: Research on long-term use of mitomycin C (MC) for recurrent esophageal stenoses is limited. We assessed the long-term efficacy and safety of local application of MC for recurrent esophageal stenoses in children. METHODS: This was a retrospective study of 39 patients (17 girls) with a median age of 19.5 months (range: 2.4-196.0) at the time of MC application. The etiologies of stenosis were esophageal atresia (n = 25), caustic ingestion (n = 9), congenital esophageal stenosis (n = 3), and other causes (n = 2). Stenosis was single in 35 (90%) patients and multiple in 4 (10%). Before MC, patients underwent multiple repeated dilations (median: 3 dilations per child [range: 2-26]) over a median period of 7 months (range: 2.6-49.3). Treatment success was defined a priori as a reduction in the number of dilations over the same period from before to after the application of MC. RESULTS: For 26 (67%) patients, the application of MC was considered a success: 102 versus 17 dilatations (P < 0.0001). Sixteen (41%) patients never required additional dilation during the follow-up after MC application (median: 3.1 years [range: 0.6-8.5]). No complication related to MC was observed. Biopsies at the site of MC application were performed at maximal follow-up in 16 patients and revealed no dysplasia. Three factors were associated with success of MC: single stenosis, short stenosis, and esophageal atresia type III. CONCLUSIONS: This study is the largest series reported showing that topical application of MC is an efficient and safe treatment for recurrent esophageal stenosis in children.

Intermediate-Term Efficacy and Tolerance of Statins in Children.

OBJECTIVES: To evaluate the intermediate-term efficacy and tolerance of statins in children and adolescents with familial hypercholesterolemia. STUDY DESIGN: A total of 131 children or adolescents treated with statins for familial hypercholesterolemia were prospectively included. The efficacy of treatment was established by the percentage of children who achieved low density lipoprotein-cholesterol (LDL-C) levels <160 mg/dL during treatment. Treatment tolerance was evaluated by the occurrence of clinical or laboratory side effects, regularity of increases in height and weight, and pubertal development. RESULTS: The median duration of treatment with statins was 4 years. A median decrease of 32% in LDL-C levels was observed (P < .0001). The therapeutic target (LDL-C <160 mg/dL) was achieved in 67% of cases. Increases in height and weight and sexual maturation were not affected by the treatment. Minor side effects were reported for 24 (18.4%) patients including 3 cases of a clinically asymptomatic increase in creatine phosphokinase (CPK) levels, 2 cases of an increase in CPK levels with muscular symptoms, 14 cases of myalgia without an increase in CPK levels, 3 cases of abdominal pain, 1 case of dysuria, and 1 case of diffuse pain. None of these side effects led to the discontinuation of statin therapy, although a change of statin was required in 7 cases. This new statin was tolerated in all cases. No patients had abnormal liver function during treatment. CONCLUSIONS: The results of this large cohort confirm the intermediate-term safety and efficacy of statin therapy in children with familial hypercholesterolemia.

[Familial hypercholesterolemia in children and adolescents]. / Hypercholestérolémie familiale chez l'enfant et l'adolescent.

Familial hypercholesterolemia in children and adolescents. Familial hypercholesterolemia is a common genetic disease. The dominant autosomal heterozygous form is most common in relation to the pathogenic mutation of a single gene responsible for a significant rise in LDL-cholesterol levels in childhood. In the absence of treatment, this abnormality exposes to a risk of early cardiovascular diseases in men and women. This pathology is totally asymptomatic in childhood. A lipid check-up should be proposed in case of a familial history of early cardiovascular diseases or severe dyslipidemia, if a mutation is already known in parents or if familial history is unknown. The diagnosis is suspected if LDL-cholesterol is > 1,6 g/L. A genetic assessment will be proposed according to family history and evolution. Management begins in childhood with the initial introduction of specific dietary measures. However, these are often insufficient requiring statin therapy from the age of 8.

Hypercholestérolémie familiale chez l'enfant et l'adolescent. L'hypercholestérolémie familiale est une maladie génétique fréquente. La forme hétérozygote autosomique dominante est la plus courante en rapport avec la mutation pathogène d'un seul gène responsable d'une élévation importante des taux du LDL-cholestérol dès l'enfance. Cette anomalie, en l'absence de prise en charge, expose à un risque d'accidents cardiovasculaires précoces chez l'homme et la femme. Cette pathologie est totalement asymptomatique dans l'enfance. Un dépistage par un bilan lipidique doit donc être proposé en cas d'antécédents familiaux d'hypercholestérolémie importante, de pathologies cardiovasculaires précoces, d'une mutation responsable d'une hypercholestérolémie familiale connue chez un des parents ou en cas d'antécédents familiaux inconnus. Le diagnostic est suspecté si le LDL-cholestérol est supérieur à 1,6 g/L. Une étude génétique est alors proposée selon l'histoire familiale et l'évolution. La prise en charge initiale se fait dès l'enfance avec la mise en place de mesures diététiques spécifiques. Celles-ci sont cependant souvent insuffisantes, nécessitant l'instauration d'un traitement par statines à partir de l'âge de 8 ans.

Contractile forces at tricellular contacts modulate epithelial organization and monolayer integrity.

Monolayered epithelia are composed of tight cell assemblies that ensure polarized exchanges. EpCAM, an unconventional epithelial-specific cell adhesion molecule, is assumed to modulate epithelial morphogenesis in animal models, but little is known regarding its cellular functions. Inspired by the characterization of cellular defects in a rare EpCAM-related human intestinal disease, we find that the absence of EpCAM in enterocytes results in an aberrant apical domain. In the course of this pathological state, apical translocation towards tricellular contacts (TCs) occurs with striking tight junction belt displacement. These unusual cell organization and intestinal tissue defects are driven by the loss of actomyosin network homoeostasis and contractile activity clustering at TCs, yet is reversed by myosin-II inhibitor treatment. This study reveals that adequate distribution of cortical tension is crucial for individual cell organization, but also for epithelial monolayer maintenance. Our data suggest that EpCAM modulation protects against epithelial dysplasia and stabilizes human tissue architecture.

Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency.

BACKGROUND: Inflammatory bowel disease (IBD) is one of the most common chronic gastrointestinal diseases, but the underlying molecular mechanisms remain largely unknown. Studies of monogenic diseases can provide insight into the pathogenesis of IBD. OBJECTIVE: We thought to determine the underlying molecular causes of IBD occurring in 2 unrelated families in association with an immune deficiency. METHODS: We performed genetic linkage analysis and candidate gene sequencing on 13 patients from a large consanguineous family affected by early-onset IBD, progressive immune deficiency, and, in some cases, autoimmunity and alopecia, a condition we named enteropathy-lymphocytopenia-alopecia. The candidate gene was also sequenced in an unrelated patient with a similar phenotype. We performed histologic analysis of patients' intestinal biopsy specimens and carried out functional assays on PBMCs. Gut organoids derived from a patient's biopsy specimen were analyzed. RESULTS: We identified biallelic missense mutations in tetratricopeptide repeat domain 7A (TTC7A) in all patients from both families. The resulting TTC7A depletion modified the proliferation, adhesion, and migratory capacities of lymphocytes through inappropriate activation of the RhoA signaling pathway. Normal function was restored by wild-type TTC7A expression or addition of a RhoA kinase inhibitor. The growth and polarity of gut epithelial organoids were also found to be dependent on the RhoA signaling pathway. CONCLUSIONS: We show that TTC7A regulates the actin cytoskeleton dynamics in lymphocytes through the RhoA signaling pathway and is required in both lymphocytes and epithelial cells for maintaining equilibrium between cell proliferation, migration, polarization, and cell death. Our study highlights variability in the phenotypic expression resulting from TTC7A deficiency and outlines that impairment of both epithelial cells and lymphocytes cooperatively causes IBD.

Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form.

Congenital tufting enteropathy (CTE) is a rare and severe enteropathy recently ascribed to mutations in the epcam gene. Here we establish SPINT2, previously ascribed to congenital sodium diarrhea, as a second gene associated with CTE and report molecular and immunohistochemistry data in 57 CTE patients. Inclusion criteria were early onset diarrhea and intestinal insufficiency with the typical histological CTE abnormalities. The clinical phenotype was registered, the entire coding regions of epcam and SPINT2 sequenced, and immunostaining of EpCAM and SPINT2 performed on intestinal biopsies. An epcam mutation was involved in 41 patients (73 %) who mainly displayed isolated digestive symptoms. Mutations severely affected gene expression since the EpCAM signal on intestinal tissues was either undetectable or low and irregular. Twelve other patients (21 %) carried mutations in SPINT2, and were phenotypically characterized by systematic association with keratitis (p < 10(-4)) and, for half of them, with choanal atresia (p < 10(-4)). Dependency on parenteral nutrition (PN) was comparable in patients with epcam or SPINT2 mutations, but the frequent epcam mutation c.556-14A>G (abnormal splicing) was significantly associated with a better outcome (p = 0.032) with milder PN dependency to weaning in some cases. Finally, four patients (7 %) with isolated digestive symptoms had no detectable epcam or SPINT2 mutation. Two candidate genes, Elf3 and Claudin7, were excluded from this population. Our study allows us to separate CTE patients into at least three genetic classes, each with specific phenotypes. The genetics approach raises the question of the distinction between two congenital enteropathies. Our findings should help improve the diagnosis of CTE, guide toward strategies of long-term PN management, and limit indications for intestinal transplantation to life-threatening PN complications.

Intractable diarrhea with tufting enteropathy: a favorable outcome is possible.

BACKGROUND AND OBJECTIVE: Tufting enteropathy (TE) is a congenital abnormality of intestinal mucosa development characterized by severe intestinal failure requiring parenteral nutrition (PN) and, in some cases, small bowel transplantation. A few patients have had a more favorable outcome. The objective of this study was to evaluate possible correlations between histological lesion severity in duodenal biopsies and clinical outcomes in children with TE. PATIENTS AND METHODS: We retrospectively reviewed the records of patients diagnosed with TE between 1993 and 2003 at our institution based on intractable neonatal-onset diarrhea with prolonged dependence on PN and duodenal biopsy findings of villous atrophy, epithelial dysplasia with enterocyte dedifferentiation and disorganization (tufting) of the surface epithelium, and crypt abnormalities. The histological lesions were assessed semiquantitatively and compared with the clinical outcomes including dependence on PN. RESULTS: Seven children, all from consanguineous parents, were studied for a median of 6.5 years. Three were permanently weaned off PN and experienced normal growth without nutritional assistance. Initial biopsies in all 3 children showed severe diffuse histological lesions. At weaning off PN, 2 of these 3 patients had persistent, although less diffuse, histological lesions. CONCLUSIONS: Progressive weaning off PN is possible in some children with TE. In our experience, this favorable outcome was not predicted by histological lesion severity, although the lesions improved in some patients. New biomarkers for identifying the histological lesions and predicting the outcome would be useful.

Membrane progestin receptors alpha and gamma in renal epithelium.

Sex hormones have broader effects than regulating reproductive functions. Recent identification of membrane progestin receptors expressed in kidney prompted us to investigate their putative involvement in the renal effects of this hormone. We first focused our investigations on mPRalpha and gamma by analyzing three parameters 1/ their distribution along the mouse nephron and their subcellular location in native kidney, 2/ the ability of progesterone to stimulate ERK pathway and/or Ca(2+) release from internal stores in native kidney structures and 3/ the cellular localization of mPRalpha and its molecular determinants in heterologous expression system. We observed that 1/ mPRalpha expression is restricted to proximal tubules of both male and female mice whereas mPRgamma exhibits a much broader expression all along the nephron except the glomerulus, 2/ mPRalpha and gamma are not localized at the plasma membrane in native kidney, 3/ this expression does not permit either progesterone-induced ERK phosphorylation or Ca(2+) release and 4/ in HEK transfected cells, mPRalpha localizes in the endoplasmic reticulum (ER) due to a C-terminal ER retention motif (-KXX). Therefore, we have characterized mPRs in kidney but their role in renal physiology remains to be elucidated.